Roles of PRIP in GABAA Receptor Signaling

Abstract

GABAA receptors are a family of ligand-gated ion channels that are pentamer composed predominantly of α, β and γ subunits. They are the major target of the endogenous inhibitory neurotransmitter (GABA, γ-aminobutyric acid) and maintain the majority of fast inhibitory ion currents in the central nervous system, in addition to being drug targets for benzodiazepines, barbiturates, alcohols, neurosteroids, and some anesthetics. Moreover, modifications in GABAA receptor function are crucial in central nervous system diseases such as anxiety disorders, sleep disturbances, and seizure disorders. Therefore it is very important to understand the molecular mechanisms underlying the maintenance of functional inhibitory synapses including GABAA receptors. We have first isolated PRIP (phospholipase C-related, but catalytically inactive protein) as a novel inositol 1,4,5-trisphosphate binding protein, and subsequently found GABARAP (GABAA receptor associated protein) as one of binding partners that binds to γ2 subunit of the receptor and thus is implicated in the clustering and trafficking of the receptor to synaptic membrane. Further studies revealed that PRIP binds β subunit of the receptors and PP1c (catalytic subunit of protein phosphatase 1). These findings have prompted us to explore the possible involvement of PRIP in modulation of GABAA receptor signaling. Here we summarize our current understanding regarding how PRIP is involved in the modification of GABAA receptor signaling on the basis of the characteristics of these interacting molecules.